Process for the preparation of medicament adsorbates

ABSTRACT

A process for preparing a medicament adsorbate by sorbing a medicament drug onto a swollen hydrated complex magnesium aluminum silicate and drying the swollen mass to a final solvent content of up to about 20% by weight of the medicament adsorbate.

FIELD OF THE INVENTION

This invention relates to a process for preparing a medicament adsorbatewhich contains a complex magnesium aluminum silicate having sorbedtherein a medicament drug.

DESCRIPTION OF THE PRIOR ART

The use of complex magnesium aluminum silicate has been taught in theliterature as a method to render bitter drug principles tasteless inliquid, tablet and chewable dosage forms which become bioavailable whenthe adsorbate reaches the low pH acid media of the stomach.

U.S. Pat. No. 3,337,402 to Zentner discloses the formation of a sedativecomposition using7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one adsorbed on acomplex magnesium aluminum silicate. Zentner notes that when the drug isfirst dissolved in a lower molecular weight monohydroxy aliphaticalcohol or in an aqueous alcohol mixture and then mixed with a complexmagnesium aluminum silicate, the bitter taste and anesthetizing effecton the tongue associated with the drug is reduced or eliminated. Zentneralso discloses that the adsorbate may be mixed with other ingredients toform lozenges, tablets, candies, capsules and suspensions.

U.S. Pat. No. 3,567,819 to Idson, et al discloses the formation of adecongestant composition using phenylpropanolamine hydrochlorideadsorbed on a complex magnesium aluminum silicate. The objectionabletaste of phenylpropanolamine hydrochloride is reduced or eliminated whenthe drug is first placed in solution and then mixed with complexmagnesium aluminum silicate to form an adsorbate. The adsorbate is thendried and used to prepare a chewable multilayered tablet.

SUMMARY OF THE INVENTION

A procedure for preparing a good tasting medicament adsorbate which maycontain up to about 35% by weight medicament compound has beenunexpectedly discovered.

This has been achieved by sorbing a solution of medicament drug into ahydrated complex magnesium aluminum silicate to form a mass which whendried is an essentially tasteless medicament adsorbate.

DETAILED DESCRIPTION

In particular, it has been found that an essentially tastelessmedicament adsorbate is produced by sorbing from about 1% to about 35%by weight of a medicament drug from a solution which has been admixedwith a hydrated swollen complex magnesium aluminum silicate sorbent toform a swollen mass. The swollen mass is dried to form an essentiallytasteless adsorbate.

While the invention is not to be limited to theoretical considerations,it is believed that the hydration and swelling of complex magnesiumaluminum silicate expands the surface area available for adsorbtion andprotects the medicament from desorption until the adsorbate isrehydrated and swollen in the digestive system.

Complex magnesium aluminum silicate flakes are actually layers ofindividual submicron platelets. These platelets are separated bymonomolecular water layers. Platelet faces are negatively charged, whilethe edges have a slight positive charge. When water is added to thecomplex magnesium aluminum silicate, it penetrates the area between theplatelets forcing them apart. The platelets are then separated by layersof water. When fully dispersed in water, the swollen complex magnesiumaluminum silicate exists as discrete platelets. The platelets because oftheir charge form a structure in which the positive platelet edges areattracted to the negative platelet faces. The resulting structureresembles a house of cards in that parallel platelets are connected byperpendicular crosslinking platelets.

In its hydrated state, all of the surface area of the sorbent plateletsis available for adsorption. This effectively increases the interstitialsorbent surface area in contact with the medicament drug. The increasedsurface area results in the formation of adsorbates with a greaterdegree of taste masking than adsorbates prepared with unhydrated complexmagnesium aluminum silicate.

The complex magnesium aluminum silicate may be hydrated prior toaddition of the medicament drug or at the same time the drug is added tothe sorbent. The medicament drug may be added to the sorbent as asolution or as a solid. If the drug is added as a solid, then thesolvent used to hydrate the sorbent must also solubilize the drug. Theorder of addition of the components of the adsorbate is not critical.The addition may be accomplished by pouring, spraying or relatedtechniques known in the art. It is critical, however, that the resultantmass of sorbent, solvent and medicament drug be mixed thoroughly untiluniform. It is also critical that the amount of water in the solvent ofthe resultant mass be at least about 50% by weight of the solvent. Ifthe amount of water is less than about 50%, the complex magnesiumaluminum silicate will not fully hydrate and the adsorbate formed willbe less taste masked.

It is believed that the sorbing of the medicament solution into thehydrated swollen complex magnesium aluminum silicate renders themedicament not available for organoleptic taste prior to passage intothe digestive tract and subsequent swelling and desorption by thegastric fluid and enzymes. The taste masking sorption effect of thisinvention is superior to the taste masking found when a medicament drugis adsorbed merely from aqueous, organic or mixed solvents onto anonhydrated nonswollen complex magnesium aluminum silicate.

In the practice of the present invention, the complex magnesium aluminumsilicate is a standard article of commerce, a typical commercial productis known as "Veegum". Veegum is a standard item of commerce and it issold under that trade name by the R. T. Vanderbuilt Company, Inc., NewYork, N.Y. Another typical commercial product is known as "Magnabrite".Magnabrite is a standard item of commerce and it is sold under thattrade name by the American Colloid Company, Skokie, Ill. The typicalaverage chemical analysis of complex magnesium aluminum silicate,conventionally expressed as oxides, maybe represented as follows:

    ______________________________________                                                               Ratio to                                                         Percent by Weight                                                                          Aluminum Oxide                                         ______________________________________                                        Silicon dioxide                                                                           55 to 70       3.2 to 35                                          Magnesium oxide                                                                           2.9 to 25      0.17 to 12.5                                       Aluminum oxide                                                                            2.0 to 17      1                                                  Ferric oxide                                                                              0.4 to 1.8                                                        Calcium oxide                                                                             1.1 to 2.4                                                        Sodium oxide                                                                              1.0 to 3.8                                                        Potassium oxide                                                                           0.2 to 1.9                                                        Ignition Loss                                                                              5.5 to 12.6                                                      ______________________________________                                    

In a preferred embodiment of the invention, the complex magnesiumaluminum silicate has the following typical chemical analysis:

    ______________________________________                                                               Ratio to                                                         Percent by Weight                                                                          Aluminum Oxide                                         ______________________________________                                        Silicon dioxide                                                                           56 to 59       14.0 to 29.5                                       Magnesium oxide                                                                           21 to 24        5.2 to 12.0                                       Aluminum oxide                                                                            2.0 to 4.0     1                                                  Ferric oxide                                                                              0.4 to 0.6                                                        Calcium oxide                                                                             1.1 to 1.5                                                        Sodium oxide                                                                              2.5 to 3.5                                                        Potassium oxide                                                                           0.5 to 1.0                                                        Ignition Loss                                                                              5.5 to 12.6                                                      ______________________________________                                    

The complex magnesium aluminum silicate of this invention is present inan amount from about 65 to about 99 percent by weight of the finaladsorbate complex. In a preferred embodiment, the complex magnesiumaluminum silicate is present in an amount of about 70 to about 90percent by weight of the final adsorbate complex and most preferablyfrom about 75 to about 85 percent.

It has been found that the particle size of the complex magnesiumaluminum silicate is not critical in preparing the adsorbates of thisinvention. While not essential the average particle size of the complexmagnesium aluminum silicate may range from about 10 to about 150microns. Such products have been found suitable to sorb sufficientquantities of the medicament solution to prepare acceptable product.

Any solvent may be used in the inventive process to prepare theadsorbate providing it is capable of dissolving the medicament drug andis miscible with water. Representative solvents include water; loweralcohols, such as methanol, ethanol, propanol, isopropanol, butanol andthe like; with water being the preferred solvent.

The medicament drugs used herein may be selected from a wide variety ofdrugs and their acid addition salts. Neutral compounds as well asorganic and inorganic salts may be used provided the drug maintains itsmedicament value and is soluble in the solvent. Exemplary acid saltsinclude hydrochloride, hydrobromide, orthophosphate, benzoate, maleate,tartrate, succinate, citrate, salicylate, sulfate and acetate.

The weight percent of the drug or its acid addition salt thereof basedon the weight of the adsorbate is preferably from about 1% to about 30%,and most preferably about 5% to about 25%, which amounts will varydepending upon the therapeutic dosage permitted.

The medicament drug may be selected from a wide range of unpleasanttasting therapeutic agents and mixtures of therapeutic agents.Nonlimiting illustrative categories and specific examples include:

(a) Analgesics, such as acetaminophen, ibuprofen, phenacetin, andsalicylamide;

(b) Antiasmatics, such as aminophylline, metaproterenol, epinephrine,and theophylline;

(c) Antitussives, such as dextromethorphan, dextromethorphanhydrobromide, noscapine, carbetapentane citrate, and chlophedianolhydrochloride;

(d) Antihistamines, such as chlorpheniramine maleate, phenindaminetartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxaminecitrate, diphenhydramine hydrochloride, promethazine, and triprolidine;

(e) Antinauseant, such as dimenhydrinate, and meclizine;

(f) Decongestants, such as phenylephrine hydrochloride,phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride,ephedrine;

(g) Various alkaloids, such as codeine phosphate, codeine sulfate andmorphine;

(h) Laxatives, such as phenolphthalein, danthron, pamabrom andbisocadyl;

(i) Anti-cholesterolemic and anti-lipid agents such as gemfibrozil;

(j) Appetite suppressants such as phenylpropanolamine hydrochloride, andcaffeine;

(k) Central nervous system stimultants such as nicotine;

(l) Expectorants such as guaifenesin;

(m) Anti-inflammatory agents such as isoxicam, meclophenamic acid andnaproxen; and

(n) Nutritional supplements, including vitamins and minerals, such asniacin, pantothenic acid, vitamin B6, thiamine hydrochloride,riboflavin, potassium iodide, potassium chloride, cupric sulfate, andferrous sulfate.

Medicaments may be used alone or in combination within the rangesspecified above to form the adsorbate.

In a preferred embodiment the medicament is the expectorant guaifenesin.

The medicament adsorbate of the invention is prepared by:

Admixing a complex magnesium aluminum silicate with a medicament drugand a sufficient amount of solvent to dissolve the medicament drug andhydrate the complex magnesium aluminum silicate to form a swollen masscontaining said drug in an adsorbed condition, said solvent having awater content of at least about 50% by weight of the solvent, drying theswollen mass to a final solvent content up to about 20% by weight of themedicament adsorbate, and recovering the medicament adsorbate.

In a preferred embodiment, the medicament adsorbate of the invention isprepared by:

(A) preparing a blend by admixing a complex magnesium aluminum silicatewith at least an equal weight of solvent to form a swollen complexmagnesium aluminum silicate,

(B) preparing a solution by dissolving the medicament drug in a solvent.

(C) sorbing the medicament drug within the swollen complex magnesiumaluminum silicate by admixing the blend with the solution to form aswollen mass having a homogenous consistency and a water content of atleast about 50% by weight of the total solvent content,

(D) drying the swollen mass to a final solvent content of up to about20% by weight of the medicament adsorbate.

(E) recovering the medicament adsorbate.

In another preferred embodiment, the medicament adsorbate of theinvention is prepared by:

(A) preparing a solution by dissolving the medicament drug in an amountof solvent at least equal in weight to the amount of complex magnesiumaluminum silicate, said solvent having a water content of at least about50% by weight of the solvent.

(B) sorbing the medicament drug within a complex magnesium aluminumsilicate by admixing the solution with the complex magnesium aluminumsilicate to form a swollen homogenous mass, and

(C) drying the swollen mass to a final solvent content of up to about20% by weight of the medicament adsorbate.

(D) recovering the medicament adsorbate.

To form the medicament drug solution, the medicament drug is admixedwith a solvent until it is dissolved. The solvent may be heated to aiddissolution. Preferably the solvent is heated from about 65° C. to about99° C.

The amount of solvent utilized to dissolve the medicament drug will varydepending on the solubility of the particular medicament drug used toform the adsorbate. The weight percent of the solvent used to form thesolution based on the medicament adsorbate is from about 10% to about60%, preferably about 15% to about 45%, and most preferably about 20% toabout 35% when the adsorbate is formed with swollen hydrated complexmagnesium aluminum silicate.

When a complex magnesium aluminum silicate-solvent blend is used in theprocess the complex magnesium aluminum silicate and solvent are admixeduntil the silicate is swollen and the mixture is uniform. The solventmay be heated to aid formation of a uniform swollen blend. Preferablythe solvent is heated from about 35° C. to about 99° C.

The amount of solvent utilized to prepare the swollen complex magnesiumaluminum silicate-solvent blend may vary widely but is generally fromabout 1 to about 20 times the weight of the complex magnesium aluminumsilicate and preferably from about 5 to about 10 times the weight.

When the third procedure, the alternative preferred procedure, describedabove is utilized, the medicament drug is dissolved in sufficientsolvent to hydrate and swell the complex magnesium aluminum silicatesorbent. The amount of solvent utilized may vary widely but is generallyfrom about 1 to about 20 times the weight of complex magnesium aluminumsilicate and preferably from about 5 to about 10 times the weight. Thesolvent must have a water content of at least about 50% by weight of thesolvent. A water content of less than about 50% will not sufficientlyhydrate and swell the complex magnesium aluminum silicate.

The process involves the step of dissolving the medicament drug in asuitable inert solvent. The resultant solution is then sorbed withmixing for about 5 to about 45 minutes into the swelled complexmagnesium aluminum silicate. The resulting product is dried to apredetermined solvent content of up to about 20% and preferably about 2%to about 15% by weight of the medicament adsorbate. Conditions forremoving the solvent are not critical. The swelled adsorbate may beheated to aid solvent removal. Preferably the adsorbate is heated fromabout 60° C. to about 95° C. most preferably from about 65° C. to about85° C.

The medicament adsorbate once prepared may be stored for future use orformulated with conventional additives, that is pharmaceuticallyacceptable carriers, to prepare medicated compositions which offer avariety of textures to suit particular applications. Such compositionsmay be in the form of a lozenge, tablet, toffee, nougat, chewy candy,chewing gum, suspension, and so forth. The pharmaceutically acceptablecarriers may be prepared from a wide range of materials. Without beinglimited thereto, such materials include diluents, binders and adhesives,lubricants, disintegrants, colorants, bulking agents, flavorings,sweeteners and miscellaneous materials such as buffers and adsorbents inorder to prepare a particular medicated composition. The preparation ofconfectionery and chewing gum products is well known and does notconstitute an essential aspect of this invention.

As used herein, the term confectionery material means a productcontaining a bulking agent selected from a wide variety of materialssuch as sugar, corn syrup, and in the case of sugarless bulking agents,sugar alcohols such as sorbitol and mannitol and mixtures thereof.Confectionery material may include such exemplary substances aslozenges, tablets, toffee, nougat, chewy candy and so forth. In general,the bulking agent will comprise from about 5 to about 99% and preferably20 to about 95% by weight of the medicated confectionery product.

Lozenges are flavored medicated dosage forms intended to be sucked andheld the mouth. They may be in the form of various shapes, the mostcommon being flat, circular, octagonal and biconvex forms. The lozengebases are generally in two forms, hard, boiled candy lozenges andcompressed tablet lozenges.

The hard boiled candy lozenges are prepared from a mixture of sugar andother carbohydrates that are kept in an amorphous or glassy condition.This form can be considered a solid syrup of sugars generally havingfrom 0.5 to about 1.5% moisture. Such materials normally contain up toabout 92% corn syrup, up to about 70% sugar and from 0.1% to about 5.0%water. The syrup component generally is prepared from corn syrups highin dextrose, but may include other materials. Further ingredients suchas flavorings, sweetener, acidulents, colorants and so forth may also beadded.

Boiled candy lozenges may also be prepared from nonfermentable sugarssuch as sorbitol, mannitol, and hydrogenated corn syrup. The candylozenges may contain up to about 95% sorbitol, a mixture of sorbitol andmannitol at a ratio of about 9.5 to 0.5 up to about 7.5 to 2.5 andhydrogenated corn syrup up to about 55% of the syrup component.

In contrast, compressed tablet lozenges contain particulate materialsand are formed into structures under pressure. They generally containsugars in amounts up to 95% and typical tablet excipients such asbinders and lubricants as well as flavors, colorants and so forth.

The lozenges may be made of soft confectionary materials such as thosecontained in nougat. These materials contain two primary components,namely a high boiling syrup such as corn syrup or the like, and arelatively light textured frappe, generally prepared from gelatin, eggalbumen, milk proteins such as casein, and vegetable proteins such assoy protein, and the like. The frappe is generally relatively light, andmay, for example, range in density from about 0.5 to about 0.7g/cc.

By comparison, the high boiling syrup, or "bob syrup," is relativelyviscous and possesses a higher density, and frequently contains asubstantial amount of sugar. Conventionally, the final nougatcomposition is prepared by the addition of the "bob syrup" to the frappeunder agitation, to form the basic nougat mixture. Further ingredientssuch as flavorings, oils, additional sugar and the like may be addedthereafter also under agitation. A general discussion of the compositionand preparation of nougat confections may be found in B. W. Minifie,CHOCOLATE, COCOA AND CONFECTIONERY: Science and Technology, 2nd edition,AVI Publishing Co., Inc., Westport, Conn., (1980), at pages 424-425,which disclosure is incorporated herein by reference.

Pharmaceutical suspensions of this invention may be prepared byconventional methods long established in the art of pharmaceuticalcompounding. Suspensions may contain conventional adjunct materialemployed in formulating the suspensions of the art. The suspensions ofthe present invention can comprise:

(a) preservatives such as benzoic acid, sorbic acid, methylparaben,propylparaben and ethylene-diaminetetracetic acid (EDTA). Preservativesare generally present in amounts up to about 1% and preferably fromabout 0.05 to about 0.5% by weight of the suspension;

(b) buffers such as citric acid-sodium citrate, phosphoric acid-sodiumphosphate, and acetic acid-sodium acetate in amounts up to about 1% andpreferably from about 0.05 to about 0.5% by weight of the suspension;

(c) suspending agents or thickeners such as cellulosics likemethylcellulose, carageenans like alginic acid and its derivatives,xanthan gums, gelatin, acacia, and microcrystalline cellulose in amountsup to about 20% and preferably from about 1% to about 15% by weight ofthe suspension:

(d) antifoaming agents such as dimethyl polysiloxane in amounts up toabout 0.2% and preferably from about 0.01 to about 0.1% by weight of thesuspension;

(e) sweeteners includes those sweeteners both natural and artificialwell known in the art.

Sweetening agents such as monosaccharides, disaccharides andpolysaccharides such as xylose, ribose, glucose, mannose, galactose,fructose, dextrose, sucrose, maltose, partially hydrolyzed starch orcorn syrup solids and sugar alcohols such as sorbitol, xylitol, mannitoland mixtures thereof may be utilized in amounts from about 10% to about60% and preferably from about 20% to about 50% by weight of thesuspension. Water soluble artificial sweeteners such as saccharin andsaccharin salts such as sodium or calcium, cyclamate salts,acesulfame-K, aspartame and the like and mixtures thereof may beutilized in amounts from about 0.001% to about 5% by weight of thesuspension;

(f) flavorants include both natural and artificial flavors, and mintssuch as peppermint, menthol, vanilla, artificial vanilla, chocolate,artificial chocolate, cinnamon, various fruit flavors, both individualand mixed may be utilized in amounts from about 0.5% to about 5% byweight of the suspension;

(g) colorants useful in the present invention include pigments which maybe incorporated in amounts of up to about 6% by weight of thecomposition. A preferred pigment, titanium dioxide, may be incorporatedin amounts up to about 1%. Also, the colorants may include other dyessuitable for food, drug and cosmetic applications, and known as F.D.&C.dyes and the like. such dyes are generally presents in amount up toabout 0.25% and preferably from about 0.05 to about 0.2% by weight ofthe suspension;

(h) decolorizing agents such as sodium metabisufite, ascorbic acid andthe like may be incorporated into the suspension to prevent colorchanges due to aging. In general, amounts up to about 0.25% andpreferably 0.05 to 0.2% by weight of the suspension are used;

(i) solubilizers such as alcohol, propylene glycol, polyethylene glycoland the like may be used to solubilize the flavors. Solubilizing agentsare generally present in amounts up to about 10%; preferably from about2% to about 5% by weight of the suspension.

Pharmaceutical suspensions of the present invention may be prepared asfollows:

(A) admixing the thickener with water heated from about 40° C. to about95° C. preferably about 40° C. to about 70° C. to form a dispersion ifthe thickener is not water soluble or a solution if the thickener iswater soluble,

(B) admix the sweetener with water to form a solution,

(C) admix the medicament adsorbate with the thickener-water admixture toform a uniform thickener-adsorbate composition,

(D) combine the sweetener solution with the thickener-adsorbatecomposition and mix until uniform,

(E) admix optional ingredients such as colorants, flavors, decolorants,solubilizers, antifoaming agents, buffers and additional water with themixture of step (D) to form the suspension.

Pharmaceutical tablets of this invention may also be in chewable form.This form is particularly advantageous because of convenience andpatient acceptance. To achieve acceptable stability and quality as wellas good taste and mouth feel several considerations are important,namely amount of active substance per tablet, flavor, compressibilityand organoleptic properties of the drug.

The preparation of chewable medicated candy is by procedures similar tothose used to make soft confectionary products. This procedure generallyinvolves the formation of a boiled sugar-corn syrup blend to which isadded a frappe mixture. The boiled sugar-corn syrup blend may beprepared from sugar and corn syrup blended in parts by weight ratio ofabout 90 to 10 to about 10 to 90. This blend is heated to temperaturesabove 121° C. to remove water and to form a molten mass. The frappe isgenerally prepared from gelatin, egg albumen, milk proteins such ascasein, and vegetable proteins such as soy protein, and the like whichare added to a gelatin solution and rapidly mixed at ambient temperatureto form an aerated sponge like mass. The frappe is then added to themolten candy base and mixed until homogenous at temperatures between 65°C. and 121° C.

The medicament adsorbate can then be added as the temperature of the mixis lowered to about 65° C. to about 135° C. whereupon additionalingredients are added such as flavors, and colorants. The formulation isfurther cooled and formed to pieces of desired dimensions.

A general discussion of the lozenge and chewable tablet forms ofconfectionary may be found in H. A. Lieberman and L. Lachman,Pharmaceutical Dosage Forms: Tablets Volume 1, Marcel Dekker, Inc., NewYork, N.Y. at pages 289 to 466 which disclosure is incorporated hereinby reference.

As used herein, the term chewing gum product means a product containinga chewing gum formulation. In general, the chewing gum formulation willcomprise from about 5 to about 99% and preferably 20 to about 95% byweight of the medicated chewing gum product.

With regard to a chewing gum formulation, such formulations contain agum base and various additives, such as sweeteners and flavors. The gumbase employed will vary greatly depending on various factors such as thetype of base used, consistency desired and other components used to makethe final product. In general, amounts of about 5% to about 45% byweight of the final chewing gum composition are acceptable for use inchewing gum compositions with preferred amounts of about 15% to about25% by weight. The gum base may be any water-insoluble gum base wellknown in the art. Illustrative examples of suitable polymers in gumbases include both natural and synthetic elastomers and rubbers. Forexample, those polymers which are suitable in gum bases, include,without limitation, substances of vegetable origin such as chicle,jelutong, gutta percha and crown gum. Synthetic elastomers such asbutadienestyrene copolymers, isobutylene-isoprene copolymers,polyethylene, polyisobutyliene and polyvinylacetate and mixturesthereof, are particularly useful.

The gum base composition may contain elastomer solvents to aid insoftening the elastomer component. Such elastomer solvents may comprisemethyl, glycerol or pentaerythritol esters of rosins or modified rosins,such as hydrogenated, dimerized or polymerized rosins or mixturesthereof. Examples of elastomer solvents suitable for use herein includethe pentaerythritol ester of partially hydrogenated wood rosin,pentaerythritol ester of wood rosin, glycerol ester of wood rosin,glycerol ester of partially dimerized rosin, glycerol ester ofpolymerized rosin, glycerol ester of tall oil rosin, glycerol ester ofwood rosin and partially hydrogenated wood rosin and partiallyhydrogenated methyl ester of rosin, such as polymers of alpha-pinene andbeta-pinene; terpene resins including polyterpene and mixtures thereof.The solvent may be employed in an amount ranging from about 10% to about75% and preferably about 45% to about 70% by weight to the gum base.

A variety of traditional ingredients such as plasticizers or softenerssuch as lanolin, stearic acid, sodium stearate, potassium stearate,glyceryl triacetate, glycerine and the like as well as natural andsynthetic waxes, petroleum waxes, such as polyurethane waxes, paraffinwaxes and microcrystalline waxes may also be incorporated into the gumbase to obtain a variety of desirable textures and consistencyproperties. These individual additional materials are generally employedin amounts of up to about 30% by weight and preferably in amounts fromabout 3% to about 20% by weight of the final gum base composition.

The chewing gum composition may additionally include the conventionaladditives of flavoring agents, coloring agents such as titanium dioxide,emulsifiers such as lecithin and glyceryl monostearate; and additionalfillers such as aluminum hydroxide, alumina, aluminum silicates, calciumcarbonate, and talc and combinations thereof. These fillers may also beused in the gum base in various amounts. Preferably the amount offillers when used will vary from about 4% to about 30% by weight of thefinal chewing gum.

In the instance where auxiliary sweeteners are utilized, the presentinvention contemplates the inclusion of those sweeteners well known inthe art, including both natural and artificial sweeteners. Thus,additional sweeteners may be chosen from the following non-limitinglist:

A. Water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose,mannose, galactose, fructose, dextrose, sucrose, maltose, partiallyhydrolyzed starch, or corn syrup solids and sugar alcohols such assorbitol, xylitol, mannitol and mixtures thereof.

B. Water-soluble artificial sweeteners such as the soluble saccharinsalts, i.e., sodium, or calcium saccharin salts, cyclamate salts,acesulfame-K and the like, and the free acid form of saccharin.

C. Dipeptide based sweeteners such as L-aspartyl-L-phenylalanine methylester and materials described in U.S. Pat. No. 3,492,131 and the like.

In general, the amount of sweetener will vary with the desired amount ofsweeteners selected for a particular chewing gum. This amount willnormally be 0.001% to about 90% by weight when using an easilyextractable sweetener. The water-soluble sweeteners described incategory A above, are preferably used in amounts of about 25% to about75% by weight, and most preferably from about 50% to about 65% by weightof the final chewing gum composition. In contrast, the artificialsweeteners described in categories B and C are used in amounts of about0.005% to about 5.0% and most preferably about 0.05% to about 2.5% byweight of the final chewing gum composition. These amounts areordinarily necessary to achieve a desired level of sweetness independentfrom the flavor level achieved from flavor oils. While water may beadded independently with dry sweetners, it will generally be added aspart of a corn syrup or corn syrup mixture.

Suitable flavorings include both natural and artificial flavors, andmints such as peppermint, spearmint, menthol, artificial vanilla,vanilla, artificial chocolate, chocolate, cinnamon, various fruitflavors, both individual and mixed, and the like are contemplated. Theflavorings are generally utilized in amounts that will vary dependingupon the individual flavor, and may, for example, range in amounts ofabout 0.5% to about 3% by weight of the final composition.

The colorants useful in the present invention, include the pigmentswhich may be incorporated in amounts of up to about 6% by weight of thecomposition. A preferred pigment, titanium dioxide, may be incorporatedin amounts of up to about 1% by weight. Also, the colorants may includeother dyes suitable for food, drug and cosmetic applications, and knownas F.D. & C. dyes and the like. The materials acceptable for theforegoing spectrum of use are preferably water-soluble. Illustrativeexamples include the indigo dye, known as F.D. & C. Blue No. 2, which isthe disodium salt of 5,5-indigotindisulfonic acid. Similarly, the dyeknown as F.D. & C. Green No. 1, comprises a triphenylmethane dye and isthe monosodium salt of 4-[4-N-ethyl-p-sulfobenzylamino)diphenylmethylene]-[1-(N-ethyl-N-p-sulfoniumbenzyl)-2,5-cyclohexadienimine].A full recitation of all F.D. & C. and D. & C. colorants and theircorresponding chemical structures may be found in the Kirk-OthmerEncyclopedia of Chemical Technology, 3rd edition, in Volume 6, at pages561-595, which text is accordingly incorporated herein by reference.

Suitable oils and fats that are usable would include partiallyhydrogenated vegetable or animal fats, such as coconut oil, palm kerneloil, beef tallow, lard, and the like. These ingredients are generallyutilized in amounts with respect to the comestible product of up toabout 7.0% by weight, and preferably up to about 3.5% by weight of thefinal product.

It is generally believed that as the required amount of active substanceper structure gets smaller and/or less bad tasting, the task at arrivingat an acceptable formulation becomes easier due to the greater number offormulations available. Alternatively, extremely bad-tasting and/orhigh-dose drugs are difficult to formulate into medicament/chewabletablets. The medicament adsorbates of this invention overcome thesedifficulties.

The quantity of adsorbate used may vary widely depending upon theparticular medicament drug dosage. Amounts of medicament of about 1.0 toabout 400 mg per medicated dosage are usable dependent upon theparticular medicament. Naturally amounts of medicament adsorbate usedwill vary depending on the therapeutic dosage required and the amount ofmedicament sorbed on the substrate. Illustrative examples are describedbelow.

The usual dosage of dextromethorphan hydrobromide is between 10 and 30mg per tablet. Incorporation of the adsorbate into, for example, a candybase is not difficult. It is compatible with most flavors and is stableover a wide pH range. The dextromethorphan HBr when added as themedicament adsorbate avoids its bitter taste and flavoring difficulty.

The usual dosage of phenylpropanolamine hydrochloride is about 12.5 to25 mg per tablet. The usual dosage of guaifenesin is 100 to 400 mg pertablet. The usual dosage of pseudoephedrine hydrochloride is 15 to 60 mgper tablet. The usual dosage range of chlorpheniramine maleate is 2 to 4mg and lends itself easily to incorporation into a candy base.Naturally, the exact amount used will vary with the particularapplication and drug. These formulations are not difficult to flavorbecause the adsorbates formed with these compounds substantiallyeliminate medicament after-taste.

The medicament adsorbate is generally present with the pharmaceuticallyacceptable carrier in an amount of from about 1% to about 60% by weightof the final composition. The exact amount will be dependent upon theparticular medicament and dosage required.

The present invention is further illustrated by the following examples.All parts and percentages in the examples and throughout thespecification and claims are by total weight of the medicament adsorbateunless otherwise indicated.

The complex magnesium aluminum silicate of Examples 1 and 2 has thefollowing typical chemical analysis:

    ______________________________________                                                               Ratio to                                                         Percent by Weight                                                                          Aluminum Oxide                                         ______________________________________                                        Silicon dioxide                                                                           56 to 59       14.0 to 29.5                                       Magnesium oxide                                                                           21 to 24        5.2 to 12.0                                       Aluminum oxide                                                                            2.0 to 4.0     1                                                  Ferric oxide                                                                              0.4 to 0.6                                                        Calcium oxide                                                                             1.1 to 1.5                                                        Sodium oxide                                                                              2.5 to 3.5                                                        Potassium oxide                                                                           0.5 to 1.0                                                        Ignition Loss                                                                              5.5 to 12.6                                                      ______________________________________                                    

EXAMPLE 1 (Inventive Run 1)

This Example demonstrates a method for preparing a quaifenesin adsorbateaccording to the process of the invention.

To 1200 grams of heated water held at about 85° C. to about 95° C. ismixed 1200 grams of complex magnesium aluminum silicate to form aswollen complex magnesium aluminum silicate. The mixing is continued forabout 15 minutes until a uniform swollen mixture results.

To 2000 grams of heated water held at about 85° C. to about 95° C. ismixed 270 grams of guaifenesin until a solution is formed.

The guaifenesin solution is mixed with the water: complex magnesiumaluminum silicate mixture until a swollen homogeneous mass is obtained.The swollen mass is then dried at about 75° C. for about 16 hours. Theresultant dried mass is then milled to produce a free flowingparticulate material having a particle size of about 100 microns.

An organoleptic evaluation test was performed on the product todetermine the presence or absence of bitterness.

The adsorbate of this example has significantly less bitterness thancomparative Example 2.

EXAMPLE 2 (Non-Inventive Run A)

This Example demonstrates a method for preparing a guaifenesin adsorbatenot according to the process of the invention.

To 1500 grams of heated water held at 85° C. is mixed 750 grams ofguaifenesin until a solution is formed. The resultant solution is thenadded with mixing to 3000 grams of complex magnesium aluminum silicate.Mixing is continued 10 minutes until a homogeneous mass is obtained .The mass is then dried at about 75° C. for about 16 hours. The resultantdried mass is then milled to produce a free flowing particulate materialhaving a particle size of about 100 microns.

An organoleptic evaluation test was performed on the product todetermine the presence or absence of bitterness.

The adsorbate of this example has an acceptable level of bitterness.

This invention being thus described, it will be obvious that the samemay be varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

I claim:
 1. A process for preparing a medicament adsorbate whichcomprises:admixing a complex magnesium aluminum silicate with amedicament drug and a sufficient amount of solvent to dissolve themedicament drug and hydrate the complex magnesium aluminum silicate toform a swollen mass containing said drug in an adsorbed condition, saidsolvent having a water content of at least about 50% by weight of thesolvent, drying the swollen mass to a final solvent content up to about20% by weight of the medicament adsorbate, and recovering the medicamentadsorbate.
 2. The process of claim 1 wherein the solvent is present inan amount from about 1 to about 20 times the weight of the complexmagnesium aluminum silicate.
 3. The process of claim 1 wherein theswollen mass is dried to a final solvent content of about 2% to about15% by weight of the medicament adsorbate.
 4. The process of claim 1which comprises: employing about 65% to about 99% by weight of complexmagnesium aluminum silicate, and about 1% to about 35% by weight ofmedicament drug, all percents herein are by weight percent of themedicament adsorbate.
 5. The process of claim 1 wherein the complexmagnesium aluminum silicate has the following typical chemical analysis:

    ______________________________________                                                               Ratio to                                                         Percent by Weight                                                                          Aluminum Oxide                                         ______________________________________                                        Silicon dioxide                                                                           55 to 70       3.2 to 35                                          Magnesium oxide                                                                           2.9 to 25      0.17 to 12.5                                       Aluminum oxide                                                                            2.0 to 17      1                                                  Ferric oxide                                                                              0.4 to 1.8                                                        Calcium oxide                                                                             1.1 to 2.4                                                        Sodium oxide                                                                              1.0 to 3.8                                                        Potassium oxide                                                                           0.2 to 1.9                                                        Ignition Loss                                                                              5.5 to 12.6                                                      ______________________________________                                    


6. The process of claim 1 wherein the complex magnesium aluminumsilicate has the following typical chemical analysis:

    ______________________________________                                                               Ratio to                                                         Percent by Weight                                                                          Aluminum Oxide                                         ______________________________________                                        Silicon dioxide                                                                           56 to 59       14.0 to 35                                         Magnesium oxide                                                                           21 to 24        5.2 to 12.0                                       Aluminum oxide                                                                            2.0 to 4.0     1                                                  Ferric oxide                                                                              0.4 to 0.6                                                        Calcium oxide                                                                             1.1 to 1.5                                                        Sodium oxide                                                                              2.5 to 3.5                                                        Potassium oxide                                                                           0.5 to 1.0                                                        Ignition Loss                                                                              5.5 to 12.6                                                      ______________________________________                                    


7. The process for preparing a medicament adsorbate which comprises:(A)preparing a blend by admixing a complex magnesium aluminum silicate withat least an equal weight of solvent to form a swollen complex magnesiumaluminum silicate, (B) preparing a solution by dissolving the medicamentdrug in a solvent, (C) sorbing the medicament drug within the swollencomplex magnesium aluminum silicate by admixing the blend with thesolution to form a swollen mass having a homogenous consistency and awater content of at least about 50% by weight of the total solventcontent, (D) drying the swollen mass to a final solvent content of up toabout 20% by weight of the medicament adsorbate, (E) recovering themedicament adsorbate.
 8. The process of claim 7 wherein the complexmagnesium aluminum silicate has the following typical chemical analysis:

    ______________________________________                                                               Ratio to                                                         Percent by Weight                                                                          Aluminum Oxide                                         ______________________________________                                        Silicon dioxide                                                                           55 to 70       3.2 to 35                                          Magnesium oxide                                                                           2.9 to 25      0.17 to 12.5                                       Aluminum oxide                                                                            2.0 to 17      1                                                  Ferric oxide                                                                              0.4 to 1.8                                                        Calcium oxide                                                                             1.1 to 2.4                                                        Sodium oxide                                                                              1.0 to 3.8                                                        Potassium oxide                                                                           0.2 to 1.9                                                        Ignition Loss                                                                              5.5 to 12.6                                                      ______________________________________                                    


9. The process of claim 7 wherein the complex magnesium aluminumsilicate has the following typical chemical analysis:

    ______________________________________                                                               Ratio to                                                         Percent by Weight                                                                          Aluminum Oxide                                         ______________________________________                                        Silicon dioxide                                                                           56 to 59       14.0 to 35                                         Magnesium oxide                                                                           21 to 24        5.2 to 12.0                                       Aluminum oxide                                                                            2.0 to 4.0     1                                                  Ferric oxide                                                                              0.4 to 0.6                                                        Calcium oxide                                                                             1.1 to 1.5                                                        Sodium oxide                                                                              2.5 to 3.5                                                        Potassium oxide                                                                           0.5 to 1.0                                                        Ignition Loss                                                                              5.5 to 12.6                                                      ______________________________________                                    


10. The process of claim 7 which comprises preparing the solution withsolvent in an amount from about 10% to about 60% by weight of thecomplex magnesium aluminum silicate, and preparing the blend withsolvent in an amount from about 1 to about 20 times the weight of thecomplex magnesium aluminum silicate.
 11. The process of claim 7 whereinthe swollen mass is dried to a final solvent content of about 2% toabout 15% by weight of the medicament adsorbate.
 12. The process forclaim 7 which comprises: employing about 65% to about 99% by weight ofcomplex magnesium aluminum silicate, and about 1% to about 35% by weightof medicament drug, all percents herein are by weight percent of themedicament adsorbate.
 13. A process for preparing a medicament adsorbatewhich comprises:(A) preparing a solution by dissolving a medicament drugin an amount of solvent at least equal in weight to the amount ofcomplex magnesium aluminum silicate said solvent having a water contentof at least about 50% by weight of the solvent, (B) sorbing themedicament drug within a complex magnesium aluminum silicate by admixingthe solution with the complex magnesium aluminum silicate to form aswollen homogenous mass, and (C) drying the swollen mass to a finalsolvent content of up to about 20% by weight of the medicamentadsorbate, (D) recovering the swollen medicament adsorbate.
 14. Theprocess of claim 13 wherein the swollen mass is dried to a final solventcontent of about 2% to about 20% by weight of the medicament adsorbate.15. The process of claim 13 which comprises: employing about 65% toabout 99% by weight of complex magnesium aluminum silicate, about 1% toabout 35% by weight of medicament drug, about 0.05% to about 4% byweight of surfactant, all percents herein are by weight percent of themedicament adsorbate.
 16. The process of claim 13 wherein the complexmagnesium aluminum silicate has the following typical chemical analysis:

    ______________________________________                                                               Ratio to                                                         Percent by Weight                                                                          Aluminum Oxide                                         ______________________________________                                        Silicon dioxide                                                                           55 to 70       3.2 to 35                                          Magnesium oxide                                                                           2.9 to 25      0.17 to 12.5                                       Aluminum oxide                                                                            2.0 to 17      1                                                  Ferric oxide                                                                              0.4 to 1.8                                                        Calcium oxide                                                                             1.1 to 2.4                                                        Sodium oxide                                                                              1.0 to 3.8                                                        Potassium oxide                                                                           0.2 to 1.9                                                        Ignition Loss                                                                              5.5 to 12.6                                                      ______________________________________                                    


17. The process of claim 13 wherein the complex magnesium aluminumsilicate has the following typical chemical analysis:

    ______________________________________                                                               Ratio to                                                         Percent by Weight                                                                          Aluminum Oxide                                         ______________________________________                                        Silicon dioxide                                                                           56 to 59       14.0 to 35                                         Magnesium oxide                                                                           21 to 24        5.2 to 12.0                                       Aluminum oxide                                                                            2.0 to 4.0     1                                                  Ferric oxide                                                                              0.4 to 0.6                                                        Calcium oxide                                                                             1.1 to 1.5                                                        Sodium oxide                                                                              2.5 to 3.5                                                        Potassium oxide                                                                           0.5 to 1.0                                                        Ingition Loss                                                                              5.5 to 12.6                                                      ______________________________________                                    


18. The process of claim 13 wherein the solvent is present in an amountfrom about 1 to about 20 times the weight of the complex magnesiumaluminum silicate.